Sex Differences in Steroid Receptor Coexpression and Circadian-Timed Activation of Kisspeptin and RFRP-3 Neurons May Contribute to the Sexually Dimorphic Basis of the LH Surge.

In rodents, the ovulation-inducing luteinizing hormone (LH) surge is sexually dimorphic, occurring only in females, but the reasons for this sex difference are unclear. Two neuropeptides, kisspeptin and RFamide-related peptide 3 (RFRP-3), are hypothesized to regulate the gonadotropin-releasing hormone (GnRH)/LH surge. In females, both of these systems show circadian changes coincident with the LH surge, but whether males show similar temporal changes under comparable hormonal conditions is unknown.

Regulation and Function of RFRP-3 (GnIH) Neurons during Postnatal Development.

RFamide-related peptide-3 (RFRP-3) [mammalian ortholog to gonadotropin-inhibiting hormone (GnIH)] potently inhibits gonadotropin secretion in mammals. Studies of RFRP-3 immunoreactivity and Rfrp expression (the gene encoding RFRP-3) in mammalian brains have uncovered several possible pathways regulating RFRP-3 neurons, shedding light on their potential role in reproduction and other processes, and pharmacological studies have probed the target sites of RFRP-3 action. Despite this, there is currently no major consensus on RFRP-3's specific endogenous role(s) in reproductive physiology.

A Novel Letrozole Model Recapitulates Both the Reproductive and Metabolic Phenotypes of Polycystic Ovary Syndrome in Female Mice.

Polycystic ovary syndrome (PCOS) pathophysiology is poorly understood, due partly to lack of PCOS animal models fully recapitulating this complex disorder. Recently, a PCOS rat model using letrozole (LET), a nonsteroidal aromatase inhibitor, mimicked multiple PCOS phenotypes, including metabolic features absent in other models. Given the advantages of using genetic and transgenic mouse models, we investigated whether LET produces a similar PCOS phenotype in mice.

Absent Progesterone Signaling in Kisspeptin Neurons Disrupts the LH Surge and Impairs Fertility in Female Mice.

Kisspeptin, encoded by Kiss1, stimulates GnRH neurons to govern reproduction. In rodents, estrogen-sensitive kisspeptin neurons in the anterior ventral periventricular nucleus and neighboring periventricular nucleus are thought to mediate sex steroid-induced positive feedback induction of the preovulatory LH surge. These kisspeptin neurons coexpress estrogen and progesterone receptors and display enhanced neuronal activation during the LH surge.

Circadian Control of the Female Reproductive Axis Through Gated Responsiveness of the RFRP-3 System to VIP Signaling.

Throughout most of the ovulatory cycle, estrogen negative feedback restrains the GnRH neuronal system. Just before ovulation, however, estrogen negative feedback is removed to permit stimulation of the preovulatory GnRH/LH surge (positive feedback) by the circadian clock in the suprachiasmatic nucleus (SCN). The mammalian ortholog of avian gonadotropin-inhibitory hormone, RFamide-related peptide 3 (RFRP-3), participates in the circadian-timed removal of estrogen negative feedback to permit the LH surge.

Examination of the influence of leptin and acute metabolic challenge on RFRP-3 neurons of mice in development and adulthood.

Background: The neuropeptide RFamide-related peptide-3 (RFRP-3; mammalian ortholog to gonadotropin-inhibiting hormone) can inhibit luteinizing hormone (LH) release and increases feeding, but the regulation and development of RFRP-3 neurons remains poorly characterized, especially in mice.

Methods And Results: We first confirmed that peripheral injections of murine RFRP-3 peptide could markedly suppress LH secretion in adult mice, as in other species. Second, given RFRP-3's reported orexigenic properties, we performed double-label in situ hybridization for metabolic genes in Rfrp neurons of mice.

Organizational and activational effects of sex steroids on kisspeptin neuron development.

Kisspeptin, encoded by the Kiss1 gene, is a neuropeptide required for puberty and adult reproductive function. Understanding the regulation and development of the kisspeptin system provides valuable knowledge about the physiology of puberty and adult fertility, and may provide insights into human pubertal or reproductive disorders. Recent studies, particularly in rodent models, have assessed how kisspeptin neurons develop and how hormonal and non-hormonal factors regulate this developmental process.

RFamide-related peptide-3 receptor gene expression in GnRH and kisspeptin neurons and GnRH-dependent mechanism of action.

RFamide-related peptide-3 (RFRP-3) is known to inhibit the activity of GnRH neurons. It is not yet clear whether its G protein-coupled receptors, GPR147 and GPR74, are present on GnRH neurons or on afferent inputs of the GnRH neuronal network or whether RFRP-3 can inhibit gonadotropin secretion independently of GnRH. We tested the following: 1) whether GnRH is essential for the effects of RFRP-3 on LH secretion; 2) whether RFRP-3 neurons project to GnRH and rostral periventricular kisspeptin neurons in mice, and 3) whether Gpr147 and Gpr74 are expressed by these neurons.

Development, sex steroid regulation, and phenotypic characterization of RFamide-related peptide (Rfrp) gene expression and RFamide receptors in the mouse hypothalamus.

Arginine-phenylalanine-amide (RFamide)-related peptide 3 (RFRP-3, encoded by the Rfrp gene) is the mammalian ortholog of gonadotropin-inhibiting hormone and can inhibit GnRH neuronal activity and LH release. However, the development and regulation of the RFRP-3 system in both sexes is poorly understood. Using in situ hybridization, we examined changes in Rfrp-expressing neurons in mice of both sexes during development and under different adulthood hormonal milieus.

Sexually dimorphic testosterone secretion in prenatal and neonatal mice is independent of kisspeptin-Kiss1r and GnRH signaling.

Kisspeptin, encoded by the Kiss1 gene, stimulates GnRH secretion and is therefore critical for sex steroid secretion at puberty and in adulthood. However, kisspeptin's role in regulating sex steroid secretion earlier in development is unexplored. In rodents, testosterone (T) levels are higher in prenatal and newborn males than females.

BAX-dependent and BAX-independent regulation of Kiss1 neuron development in mice.

The Kiss1 gene and its product kisspeptin are important regulators of reproduction. In rodents, Kiss1 is expressed in the hypothalamic arcuate (ARC) and anteroventral periventricular (AVPV)/rostral periventricular (PeN) nuclei. In the AVPV/PeN, females have more Kiss1 and tyrosine hydroxylase (TH) neurons than males.

In vivo osteopontin-induced macrophage accumulation is dependent on CD44 expression.

In order to assess the role of osteopontin (OPN) in leukocyte accumulation in inflammatory conditions, native OPN and its thrombin cleaved form (OPN+Thr) were studied in vivo using a rodent subcutaneous air pouch model (AP). Both forms of OPN-induced macrophage infiltration into the AP in wild-type mice. In animals lacking CD44, macrophage numbers were significantly reduced within the cavity, but cells still accumulated along the subcutaneous lining.